Process for production of 4-oxoquinoline compound

ABSTRACT

The present invention provides a compound useful as a synthetic intermediate for an anti-HIV agent having an integrase inhibitory activity, a production method thereof, and a production method of an anti-HIV agent using the synthetic intermediate. Specifically, the present invention provides, for example, compounds represented by the formulas (6), (7-1), (7-2) and (8): 
     
       
         
         
             
             
         
       
     
     wherein R is a fluorine atom or a methoxy group, R 1  is a C 1 -C 4  alkyl group, R 2  is a hydroxyl-protecting group, and X 2  is a halogen atom, a production method thereof, and a production method of an anti-HIV agent using the synthetic intermediate.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a compound useful as a synthesisintermediate for an anti-HIV agent having an integrase inhibitoryactivity and a production method thereof. In addition, the presentinvention relates to a production method of an anti-HIV agent using thesynthesis intermediate and the like.

BACKGROUND OF THE INVENTION

Patent reference 1 discloses a production method of a 4-oxoquinolinecompound represented by the formula [II]:

wherein each symbol is as defined in patent reference 1 (hereinaftersometimes to be abbreviated as compound [II]). Specifically, thefollowing production methods are known.Production method 1-1 (see patent reference 1: page 67)

Each symbol in the scheme is as defined in patent reference 1.

This production method is also described in patent reference 2, page 64(each symbol in the scheme is also defined in patent reference 2).

Production method 1-2 Example of production method using compound [9],into which hydroxyl-protecting group has been introduced (see patentreference 1: page 71)

Each symbol in the scheme is as defined in patent reference 1.

This production method is also described in patent reference 2, page 68(each symbol in the scheme is also defined in patent reference 2).

Production method 2-1 (see patent reference 1: page 72)

Each symbol in the scheme is as defined in patent reference 1.

This production method is also described in patent reference 2, page 69(each symbol in the scheme is also defined in patent reference 2).

Production method 2-2 Example of production method includingintroduction•deprotection step of hydroxyl-protecting group (see patentreference 1: page 74)

Each symbol in the scheme is as defined in patent reference 1.

This production method is also described in patent reference 2, page 72(each symbol in the scheme is also defined in patent reference 2).

Production method 3 (see patent reference 1: page 76)

Each symbol in the scheme is as defined in patent reference 1.

This production method is also described in patent reference 2, page 74(each symbol in the scheme is also defined in patent reference 2).

Production method 4 (see patent reference 1: page 77)

Examples of the production methods of the above-mentioned compound [12]are specifically shown in the following.

Each symbol in the scheme is as defined in patent reference 1.

Production method 5 (see patent reference 1: page 79)

Each symbol in the scheme is as defined in patent reference 1.

This production method is also described in patent reference 2, page 78(each symbol in the scheme is also defined in patent reference 2).

The above-mentioned production method 1-1 and production method 2-1relate to production methods of compound [1-2] and compound [1-5],respectively, which correspond to the above-mentioned compound [II].

In production method 1-2, production method 2-2 and production method 5,examples of production via introduction-deprotection of ahydroxyl-protecting group are shown.

In addition, production method 3 discloses a method of introducing asubstituent after 4-oxoquinoline ring formation, and production method 4describes example of a more specific production method of compound [12].

In addition, patent reference 1 discloses, of compound [II],6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (hereinafter sometimes to be abbreviated as compound (10)) as oneof the compounds particularly useful as an anti-HIV agent, and aproduction method thereof.

Specifically, Example 4-32 of patent reference 1 describes the followingproduction example.

In addition, production of 2,4-difluoro-5-iodobenzoic acid, which is astarting material, is disclosed in patent reference 1, Example 4-33,step 1.

wherein NIS is N-iodosuccinimide, catalyst shows a catalyst, and othersymbols are as defined in patent reference 1.

This production method is also described in patent reference 2, page112, Reference Example 9.

As a production method similar to this production method, patentreference 3, page 23, Example 2-1 describes a production method whereinthe hydroxyl-protecting group is a tert-butyl dimethylsilyl group. Inaddition, patent reference 3, page 12, Reference Example 1; page 17,Example 1 and page 39 and Example 2-4 describe a method of directlyproducing compound (10) from a compound wherein the hydroxyl-protectinggroup is a tert-butyldimethylsilyl group.

Moreover, patent reference 1, page 81, Reference Example 1, and patentreference 2, page 80 or Reference Example 1 disclose that2,3-dichlorobenzylzinc chloride which is an analog of3-chloro-2-fluorobenzylzinc bromide produced in the above-mentioned step6 can be produced in the same manner from 2,3-dichlorobenzyl chloride.

Patent reference 3 discloses a production method of compound (10).

Specifically, patent reference 3, Example 2-2, page 28 describes thefollowing production example.

wherein DBU is 1,8-diazabicyclo[5.4.0]undecene, catalyst shows acatalyst, and other symbols are as defined in patent reference 3.

Patent reference 1, patent reference 2 and patent reference 3 discloseproduction methods of compound (10). The references have the followingaspects.

-   -   In the final step (alkoxylation, particularly methoxylation), a        dimer is by-produced depending on the base to be used. Thus, in        this event, a removal step of the by-produced dimmer is further        necessary, which decreases the yield greatly.    -   When sodium fluoride by-produced in the final step        (alkoxylation, particularly methoxylation) is acidified in the        treatment step, hydrofluoric acid is produced, which corrodes        the production facility. Thus, a removal operation of sodium        fluoride is essential and the operation is complicated.    -   There is a concern about an unfavorable influence of        hydrofluoric acid produced in the ring-closing step on the        production facility, and therefore, the method is not of a level        satisfactory as an industrial production method.    -   Removal of the product by-produced in a reaction to insert        compound [IIb] is complicated (since alkyl zinc derivative is        used with a palladium catalyst, an operation to remove zinc salt        and palladium salt as impurities is necessary and the operation        is complicated).    -   Plural operations are necessary to protect hydroxyl group with        methyl chloroformate in a preliminary step of the reaction to        insert compound [IIb], and to deprotect the group in a later        step, and the operation is complicated.    -   A step using 3-chloro-2-fluorobenzyl bromide for the production        of compound [IIb] is not benefical for industrial production        since the compound shows high tearing property.

The above-mentioned production methods including these steps areassociated with many aspects to be improved for industrial production,and the development of a more superior production method of compound(10) is desired.

In addition, while non-patent reference 1 describes the following4-oxoquinoline compound and the like, the compounds (8) and (9) of thepresent invention, which are explained in detail in the following, arenot described.

In addition, while Example 1 (1c) of patent reference 4 describes thefollowing acrylic acid ester and the like, the compounds (6) {(6-A) and(6-B)}, and (7-1) of the present invention, which are explained indetail in the following, are not described.

Moreover, patent reference 5 describes a production example of4-oxoquinoline skeleton from the following acrylic acid ester and thelike, in a ring-closing reaction during formation of 4-oxoquinolineskeleton. However, a production method from compound (7-1) to compound(8) and a production method from compound (6-B) to compound (7-2) likethose in the present invention explained in detail in the following arenot described.

-   [Patent reference 1] WO 04/046115-   [Patent reference 2] WO 05/113509-   [Patent reference 3] WO 05/113508-   [Patent reference 4] WO 03/043992 (page 195, line 10)-   [Patent reference 5] U.S. Pat. No. 4,695,646 (column 15, line 40)-   [Non-patent reference 1] Folia Microbiologica, vol. 19, number 4,    pages 281-291, 1974 (page 282, FIG. 1)

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a compound useful as asynthetic intermediate for an anti-HIV agent having an integraseinhibitory activity and a production method thereof, and a productionmethod of an anti-HIV agent using the synthetic intermediate.

Means of Solving the Problems

In view of the above-mentioned object, the present inventors haveconducted intensive studies in an attempt to find an improved productionmethod of the above-mentioned compound [II], particularly compound (10),and found that compounds represented by the formulas (6), (7-1), (7-2)and (8) (hereinafter sometimes to be abbreviated as compounds (6),(7-1), (7-2) and (8), respectively) are useful as syntheticintermediates therefor, which resulted in the completion of the presentinvention.

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup, R² is a hydroxyl-protecting group and X² is a halogen atom.

More specifically, the present invention is as shown in the following[1]-[71], [A1]-[A26] and [B1]-[B30].

[1] Use of a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom (hereinafter sometimes to be abbreviated ascompound (7-1)), for the production of compound (10):

or a salt thereof.[2] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom (hereinaftersometimes to be abbreviated as compound (6-B)), for the production ofcompound (10)

or a salt thereof.[3] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom (hereinafter sometimes to be abbreviated ascompound (8)), for the production of compound (10):

or a salt thereof.[4] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, for the production of compound (10):

or a salt thereof.[5] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen, for theproduction of compound (10):

or a salt thereof.[6] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group(hereinafter sometimes to be abbreviated as compound (9)), and acompound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, for the production of compound (10):

or a salt thereof.[7] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, for the production of compound (10):

or a salt thereof.[8] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, for theproduction of compound (10):

or a salt thereof.[9] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a compound represented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogen atom(hereinafter sometimes to be abbreviated as compound (3)), for theproduction of compound (10):

or a salt thereof.[10] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a compound represented by the formula (3-A):

wherein X² is a halogen atom (hereinafter sometimes to be abbreviated ascompound (3-A)), for the production of compound (10):

or a salt thereof.[11] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, and acompound represented by the formula (3-B):

wherein X² is a halogen atom (hereinafter sometimes to be abbreviated ascompound (3-B)), for the production of compound (10):

or a salt thereof.[12] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom (hereinafter sometimes to be abbreviatedas compound (4)), or a salt thereof, and a compound represented by theformula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, for the production of compound (10):

or a salt thereof.[13] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom (hereinaftersometimes to be abbreviated as compound (4-A)), or a salt thereof, and acompound represented by the formula (3-A):

wherein X² is a halogen atom, for the production of compound (10):

or a salt thereof.[14] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom (hereinaftersometimes to be abbreviated as compound (4-B)), or a salt thereof, and acompound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of compound (10):

or a salt thereof.[15] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom (hereinafter sometimes to be abbreviatedas compound (5)), and a compound represented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, for the production of compound (10):

or a salt thereof.[16] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom (hereinaftersometimes to be abbreviated as compound (5-A)), and a compoundrepresented by the formula (3-A):

wherein X² is a halogen atom, for the production of compound (10):

or a salt thereof.[17] Use of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom (hereinaftersometimes to be abbreviated as compound (5-B)), and a compoundrepresented by the formula (3-B):

wherein X² is a halogen atom, for the production of compound (10):

or a salt thereof.[18] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom (hereinafter sometimes to be abbreviatedas compound (6)), a compound represented by the formula (5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, a compound represented by the formula(4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, or a salt thereof, and a compoundrepresented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, for the production of compound (10):

or a salt thereof.[19] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom (hereinaftersometimes to be abbreviated as compound (6-A)), a compound representedby the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-A):

wherein X² is a halogen atom, for the production of compound (10):

or a salt thereof.[20] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom (hereinaftersometimes to be abbreviated as compound (7-2)), a compound representedby the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of compound (10):

or a salt thereof.[21] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, a compound represented by the formula(5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, a compound represented by the formula(4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, or a salt thereof, and a compoundrepresented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, a compound represented by the formula (2):

wherein R is a fluorine atom or a methoxy group and X² is a halogen atom(hereinafter to be sometimes abbreviated as compound (2)), or a saltthereof, and a compound represented by the formula (1):

wherein R is a fluorine atom or a methoxy group (hereinafter sometimesto be abbreviated as compound (1)), or a salt thereof, for theproduction of compound (10):

or a salt thereof.[22] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-A):

wherein X² is a halogen atom, a compound represented by the formula(2-A):

wherein X² is a halogen atom (hereinafter sometimes to be abbreviated ascompound (2-A)), or a salt thereof, and compound (1-A):

or a salt thereof, for the production of compound (10):

or a salt thereof.[23] Use of a compound represented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a to saltthereof, a compound represented by the formula (3-B):

wherein X² is a halogen atom, a compound represented by the formula(2-B):

wherein X² is a halogen atom (hereinafter sometimes to be abbreviated ascompound (2-B)), or a salt thereof, and compound (1-B):

or a salt thereof, for the production of compound (10):

or a salt thereof.[24] Use of a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, for the production of a compound represented bythe formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[25] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, for theproduction of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[26] Use of a compound represented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, for the production of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[27] Use of a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a compound represented by the formula (3-A):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₂-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[28] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, and acompound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[29] Use of a compound represented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, and a compound represented by the formula (4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, or a salt thereof, for the production ofa compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[30] Use of a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-A):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[31] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[32] Use of a compound represented by the formula (5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, and a compound represented by theformula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, for the production of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[33] Use of a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, and acompound represented by the formula (3-A):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[34] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, and acompound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[35] Use of a compound represented by the formula (6):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, a compound represented by the formula(5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, a compound represented by the formula(4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, or a salt thereof, and a compoundrepresented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, for the production of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[36] Use of a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-A):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[37] Use of a compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[38] Use of a compound represented by the formula (6):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, a compound represented by the formula(5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, a compound represented by the formula(4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, or a salt thereof, a compoundrepresented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, a compound represented by the formula (2):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom, or a salt thereof, and a compound represented by the formula (1):

wherein R is a fluorine atom or a methoxy group, or a salt thereof, forthe production of a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[39] Use of a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, a compound represented by the formula (6-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, a compound represented by the formula (3-A):

wherein X² is a halogen atom, a compound represented by the formula(2-A):

wherein X² is a halogen atom, or a salt thereof, and compound (1-A):

or a salt thereof, for the production of a compound represented by theformula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[40] Use of a compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, a compound represented by the formula (3-B):

wherein X² is a halogen atom, a compound represented by the formula(2-B):

wherein X² is a halogen atom, or a salt thereof, and compound (1-B):

or a salt thereof, for the production of a compound represented by theformula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[41] Use of a compound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom.[42] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, and acompound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom. [43] Use ofa compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom.[44] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, and acompound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom.[45] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, and a compound represented by the formula (3-B):

wherein X² is a halogen atom, for the production of a compoundrepresented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom.[46] Use of a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, a compound represented by the formula (3-B):

wherein X² is a halogen atom, a compound represented by the formula(2-B):

wherein X² is a halogen atom, or a salt thereof, and compound (1-B):

or a salt thereof, for the production of a compound represented by theformula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom.[47] A method of producing compound (10)

or a salt thereof, comprising producing the compound from a compoundrepresented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[48] A method of producing compound (10)

or a salt thereof, comprising producing the compound from a compoundrepresented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom.[49] A method of producing compound (10)

or a salt thereof, comprising producing the compound from a compoundrepresented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[50] A method of producing compound (10):

or a salt thereof, which comprises a step of producing a compoundrepresented by the formula (9):

wherein R¹ is a C₁-C₄ alkyl group and R² is a hydroxyl-protecting group,from a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, and a step of producing compound (10) or a saltthereof from compound (9).[51] The production method of the above-mentioned [50], furthercomprising a step of producing compound (8) from a compound representedby the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[52] The production method of the above-mentioned [50], furthercomprising a step of producing a compound represented by the formula(7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, from acompound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, and a stepof producing compound (8) from compound (7-2).[53] The production method of the above-mentioned [51], furthercomprising a step of producing a compound represented by the formula(4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, from a compound represented by the formula (3-A):

wherein X² is a halogen atom,a step of producing a compound represented by the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (4-A) or a salt thereof,a step of producing a compound represented by the formula (6-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (5-A), and a step of producing compound (7-1) from compound(6-A).[54] The production method of the above-mentioned [53], furthercomprising a step of producing a compound represented by the formula(2-A):

wherein X² is a halogen atom, or a salt thereof, from compound (1-A):

or a salt thereof, and a step of producing a compound represented by theformula (3-A):

wherein X² is a halogen atom, from compound (2-A) or a salt thereof.[55] The production method of the above-mentioned [52], furthercomprising a step of producing a compound represented by the formula(4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, from a compound represented by the formula (3-B):

wherein X² is a halogen atom,a step of producing a compound represented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (4-B) or a salt thereof, and a step of producing compound (6-B)from compound (5-B).[56] The production method of the above-mentioned [55], furthercomprising a step of producing a compound represented by the formula(2-B):

wherein X² is a halogen atom, or a salt thereof, from compound (1-B):

or a salt thereof, and a step of producing a compound represented by theformula (3-B):

wherein X² is a halogen atom, from compound (2-B) or a salt thereof.[57] A method of producing a compound represented by the formula (8)

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, comprising producing the compound from a compoundrepresented by the formula (3):

wherein R is a fluorine atom or a methoxy group and X² is a halogenatom.[58] A method of producing a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, comprising a step of producing a compoundrepresented by the formula (4-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, from a compound represented by the formula (3-A):

wherein X² is a halogen atom,a step of producing a compound represented by the formula (5-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (4-A) or a salt thereof,a step of producing a compound represented by the formula (6-A):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (5-A),a step of producing a compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, from compound (6-A), and a step of producingcompound (8) from compound (7-1).[59] A method of producing a compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom, comprising a step of producing a compoundrepresented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, from a compound represented by the formula (3-B):

wherein X² is a halogen atom,a step of producing a compound represented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (4-B) or a salt thereof,a step of producing a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (5-B),a step of producing a compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (6-B), anda step of producing compound (8) from compound (7-2).[60] The production method of the above-mentioned [58], furthercomprising a step of producing a compound represented by the formula(2-A):

wherein X² is a halogen atom, or a salt thereof, from compound (1-A):

or a salt thereof, and a step of producing a compound represented by theformula (3-A):

wherein X² is a halogen atom, from compound (2-A) or a salt thereof.[61] The production method of the above-mentioned [59], furthercomprising a step of producing a compound represented by the formula(2-B):

wherein X² is a halogen atom, or a salt thereof, from compound (1-B):

or a salt thereof, and a step of producing a compound represented by theformula (3-B):

wherein X² is a halogen atom, from compound (2-B) or a salt thereof.

-   [62] A method of producing a compound represented by the formula    (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, comprisingproducing the compound from a compound represented by the formula (3-B):

wherein X² is a halogen atom.[63] A method of producing a compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, comprising astep of producing a compound represented by the formula (4-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, or a saltthereof, from a compound represented by the formula (3-B):

wherein X² is a halogen atom,a step of producing a compound represented by the formula (5-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (4-B) or a salt thereof,a step of producing a compound represented by the formula (6-B):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (5-B), anda step of producing a compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom, fromcompound (6-B).[64] The production method of the above-mentioned [63], furthercomprising a step of producing a compound represented by the formula(2-B):

wherein X² is a halogen atom, or a salt thereof, from compound (1-B):

or a salt thereof, and a step of producing a compound represented by theformula (3-B):

wherein X² is a halogen atom, from compound (2-B) or a salt thereof.[65] A compound represented by the formula (3-B):

wherein X² is a halogen atom.[66] A compound represented by the formula (4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom, or a salt thereof.

[67] A compound represented by the formula (5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom.[68] A compound represented by the formula (6):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup and X² is a halogen atom.[69] A compound represented by the formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[70] A compound represented by the formula (7-2):

wherein R¹ is a C₁-C₄ alkyl group and X² is a halogen atom.[71] A compound represented by the formula (8):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group andX² is a halogen atom.[A1] Use of compound (7-1) for the production of compound (10)or a salt thereof.[A2] Use of compound (7-1) and compound (8) for the production ofcompound (10) or a salt thereof.[A3] Use of compound (7-1), compound (8) and compound (9) for theproduction of compound (10) or a salt thereof.[A4] Use of compound (3-A) and compound (7-1) for the production ofcompound (10) or a salt thereof.[A5] Use of compound (3-A), compound (7-1) and compound (8) for theproduction of compound (10) or a salt thereof.[A6] Use of compound (3-A), compound (4-A) or a salt thereof, compound(7-1) and compound (8) for the production of compound (10) or a saltthereof.[A7] Use of compound (3-A), compound (5-A), compound (7-1) and compound(8) for the production of compound (10) or a salt thereof.[A8] Use of compound (3-A), compound (4-A) or a salt thereof, compound(5-A), compound (6-A), compound (7-1), compound (8) and compound (9) forthe production of compound (10) or a salt thereof.[A9] Use of compound (1-A) or a salt thereof, compound (2-A) or a saltthereof, compound (3-A), compound (4-A) or a salt thereof, compound(5-A), compound (6-A), compound (7-1), compound (8) and compound (9) forthe production of compound (10) or a salt thereof.[A10] Use of compound (3-A) for the production of compound (8).[A11] Use of compound (3-A) and compound (7-1) for the production ofcompound (8).[A12] Use of compound (3-A), compound (4-A) or a salt thereof, andcompound (7-1) for the production of compound (8).[A13] Use of compound (3-A), compound (5-A) and compound (7-1) for theproduction of compound (8).[A14] Use of compound (3-A), compound (4-A) or a salt thereof, compound(5-A), compound (6-A) and compound (7-1) for the production of compound(8).[A15] Use of compound (1-A) or a salt thereof, compound (2-A) or a saltthereof, compound (3-A), compound (4-A) or a salt thereof, compound(5-A), compound (6-A) and compound (7-1) for the production of compound(8).[A16] Compound (6-A) or compound (7-1).[A17] The compound described in the above-mentioned [A16], which is

[A18] Compound (8) or compound (9).[A19] The compound described in the above-mentioned [A18], which is

[A20] A method of producing compound (10) or a salt thereof, comprisingproducing the compound from compound (7-1).[A21] The production method of the above-mentioned [A20], comprising astep of producing compound (8) from compound (7-1); a step of producingcompound (9) from compound (8); and a step of producing compound (10) ora salt thereof from compound (9).[A22] A method of producing compound (10) or a salt thereof, comprisinga step of producing compound (4-A) or a salt thereof from compound(3-A); a step of producing compound (5-A) from compound (4-A) or a saltthereof; a step of producing compound (6-A) from compound (5-A); a stepof producing compound (7-1) from compound (6-A); a step of producingcompound (8) from compound (7-1); a step of producing compound (9) fromcompound (8); and a step of producing compound (10) or a salt thereoffrom compound (9).[A23] The production method of the above-mentioned [A22], furthercomprising a step of producing compound (2-A) or a salt thereof fromcompound (1-A) or a salt thereof; and a step of producing compound (3-A)from compound (2-A) or a salt thereof.[A24] A method of producing compound (8), comprising producing thecompound from compound (3-A).[A25] A method of producing compound (8), comprising a step of producingcompound (4-A) or a salt thereof from compound (3-A); a step ofproducing compound (5-A) from compound (4-A) or a salt thereof; a stepof producing compound (6-A) from compound (5-A); a step of producingcompound (7-1) from compound (6-A); and a step of producing compound (8)from compound (7-1).[A26] The production method described in the above-mentioned[A25], further comprising a step of producing compound (2-A) or a saltthereof from compound (1-A) or a salt thereof; and a step of producingcompound (3-A) from compound (2-A) or a salt thereof.[B1] Use of compound (6-B) for the production of compound (10)or a salt thereof.[B2] Use of compound (6-B) and compound (7-2) for the production ofcompound (10) or a salt thereof.[B3] Use of compound (6-B) and compound (8) for the production ofcompound (10) or a salt thereof.[B4] Use of compound (6-B), compound (7-2), compound (8) and compound(9) for the production of compound (10) or a salt thereof.[B5] Use of compound (3-B) and compound (6-B) for the production ofcompound (10) or a salt thereof.[B6] Use of compound (3-B), compound (4-B) or a salt thereof, andcompound (6-B) for the production of compound (10) or a salt thereof.[B7] Use of compound (3-B), compound (5-B) and compound (6-B) for theproduction of compound (10) or a salt thereof.[B8] Use of compound (3-B), compound (4-B) or a salt thereof, compound(6-B) and compound (7-2) for the production of compound (10) or a saltthereof.[B9] Use of compound (3-B), compound (4-B) or a salt thereof, compound(6-B) and compound (8) for the production of compound (10) or a saltthereof.[B10] Use of compound (3-B), compound (5-B), compound (6-B) and compound(7-2) for the production of compound (10) or a salt thereof.[B11] Use of compound (3-B), compound (5-B), compound (6-B) and compound(8) for the production of compound (10) or a salt thereof.[B12] Use of compound (3-B), compound (4-B) or a salt thereof, compound(5-B), compound (6-B), compound (7-2), compound (8) and compound (9) forthe production of compound (10) or a salt thereof.[B13] Use of compound (1-B) or a salt thereof, compound (2-B) or a saltthereof, compound (3-B), compound (4-B) or a salt thereof, compound(5-B), compound (6-B), compound (7-2), compound (8) and compound (9) forthe production of compound (10) or a salt thereof.[B14] Use of compound (3-B) for the production of compound (7-2).[B15] Use of compound (3-B) and compound (6-B) for the production ofcompound (7-2).[B16] Use of compound (3-B), compound (4-B) or a salt thereof, andcompound (6-B) for the production of compound (7-2).[B17] Use of compound (3-B), compound (5-B) and compound (6-B) for theproduction of compound (7-2).[B18] Use of compound (3-B), compound (4-B) or a salt thereof, compound(5-B) and compound (6-B) for the production of compound (7-2).[B19] Use of compound (1-B) or a salt thereof, compound (2-B) or a saltthereof, compound (3-B), compound (4-B) or a salt thereof, compound(5-B) and compound (6-B) for the production of compound (7-2).

[B20] Compound (6-B).

[B21] The compound of the above-mentioned [B20], which is

[B22] Compound (7-2).

[B23] The compound of the above-mentioned [B22], which is

[B24] A method of producing compound (10) or a salt thereof, comprisingproducing the compound from compound (6-B).[B25] The production method of the above-mentioned [B24], comprising astep of producing compound (7-2) from compound (6-B); a step ofproducing compound (8) from compound (7-2); a step of producing compound(9) from compound (8); and a step of producing compound (10) or a saltthereof from compound (9).[B26] A method of producing compound (10) or a salt thereof, comprisinga step of producing compound (4-B) or a salt thereof from compound(3-B); a step of producing compound (5-B) from compound (4-B) or a saltthereof; a step of producing compound (6-B) from compound (5-B); a stepof producing compound (7-2) from compound (6-B); a step of producingcompound (8) from compound (7-2); a step of producing compound (9) fromcompound (8); and a step of producing compound (10) or a salt thereoffrom compound (9).[B27] The production method of the above-mentioned [B26], furthercomprising a step of producing compound (2-B) or a salt thereof fromcompound (1-B) or a salt thereof; and a step of producing compound (3-B)from compound (2-B) or a salt thereof.[B28] A method of producing compound (7-2), comprising producing thecompound from compound (3-B).[B29] A production method of compound (7-2), comprising a step ofproducing compound (4-B) or a salt thereof from compound (3-B); a stepof producing compound (5-B) from compound (4-B) or a salt thereof; astep of producing compound (6-B) from compound (5-B); and a step ofproducing compound (7-2) from compound (6-B).[B30] The production method of the above-mentioned [B29], furthercomprising a step of producing compound (2-B) or a salt thereof fromcompound (1-B) or a salt thereof; and a step of producing compound (3-B)from compound (2-B) or a salt thereof.

Effect of the Invention

The present invention can provide novel compounds (6), (7-1), (7-2) and(8) useful as synthetic intermediates for anti-HIV agents (compounds)having an integrase inhibitory activity, production methods of thesynthetic intermediates, and production methods of anti-HIV agents(compounds) (e.g., compound (10) and the like) using the syntheticintermediates.

The present invention can provide an industrially highly valuableproduction method of an anti-HIV agent (compound). For example, using anintermediate compound having a methoxy group in advance as a syntheticintermediate for the production of compound (10), which is an anti-HIVagent (compound), a decrease in the yield due to the final step(alkoxylation, particularly methoxylation) in the prior art andby-production of sodium fluoride can be avoided. Using compound (6-A)and/or compound (7-1) in a ring closure step, moreover, the generationof hydrogen fluoride (HF) that causes corrosion of the productionfacility can be avoided, whereby problems in the prior art (avoidance ofdecreased yield, corrosion of production facility, etc.) can beovercome.

Further, the present invention can also provide production methods ofthe above-mentioned synthetic intermediates.

Since the above-mentioned synthetic intermediates can overcome theabove-mentioned problems in the prior art during the production of ananti-HIV agent (compound), a production method of the syntheticintermediate also has a high value for industrial application and issignificant.

Of the synthetic intermediates, compound (7-2) and compound (8) arestable by themselves, and can tolerate severe conditions and/orlong-term preservation. Furthermore, since the quality thereofinfluences the progress of a palladium catalyst reaction in the nextstep, and is also directly related to the quality of anti-HIV agents(compounds) (e.g., compound (10) and the like), they are extremelyimportant intermediate compounds.

Moreover, highly distributable compound (1) is used as a startingmaterial in the present invention. Thus, the production method of thepresent invention can produce an anti-HIV agent (compound) moreeconomically, since stability of supply of the starting material can beimproved.

BEST MODE FOR EMBODYING THE INVENTION Detailed Description of theInvention

The terms and symbols to be used in the present invention are defined inthe following.

A “halogen atom” means a fluorine atom, a chlorine atom, a bromine atomor an iodine atom.

A “C₁-C₄ alkyl group” means a straight chain or branched chain alkylgroup having 1 to 4 carbon atoms, and specific examples include methylgroup, ethyl group, propyl group, isopropyl group, butyl group, isobutylgroup, sec-butyl group and tert-butyl group.

A “hydroxyl-protecting group” means a general hydroxyl-protecting groupknown to those of ordinary skill in the art, which is introduced toprevent reaction of the hydroxyl group. Examples thereof include theprotecting groups described in Protective Groups in Organic Synthesis,published by John Wiley and Sons (1980) and the like, and specificexamples thereof include ether-protecting groups such astetrahydropyranyl group, methoxymethyl group and the like;carbonate-protecting groups such as methylcarbonate group,ethylcarbonate group and the like; silicon-protecting groups such astrimethylsilyl group, tert-butyldimethylsilyl group,tert-butyldiphenylsilyl group, etc. and the like.

R is a fluorine atom or a methoxy group.

R¹ is a “C₁-C₄ alkyl group”, preferably a methyl group or an ethylgroup.

R² is a “hydroxyl-protecting group”, preferably a silicon protectinggroup, more preferably a tert-butyldimethylsilyl group.

X¹ is a “halogen atom”, preferably a chlorine atom or a bromine atom.

X² is a “halogen atom”, preferably a bromine atom or an iodine atom,more preferably a bromine atom.

Compound (1) [compounds (1-A) and (1-B)], compound (2) [compounds (2-A)and (2-B)], compound (4) [compounds (4-A) and (4-B)] and compound (10)used or produced in the present invention may be in the form of salts.

The “salt” may be any nontoxic salt as long as it can be formed from thecompound to be used in the present invention and, for example, saltsobtained by reaction with inorganic acids such as hydrochloric acid,sulfuric acid, phosphoric acid, hydrobromic acid and the like; organicacids such as oxalic acid, malonic acid, citric acid, fumaric acid,lactic acid, malic acid, succinic acid, tartaric acid, acetic acid,trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonicacid, benzenesulfonic acid and the like; inorganic bases such as sodiumhydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide,ammonium hydroxide and the like; organic bases such as methylamine,diethylamine, triethylamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and thelike; amino acid such as lysin, arginine, alanine and the like, and thelike can be mentioned. The compound used in the present invention alsoencompasses a water-containing product, a hydrate and a solvate of eachcompound.

In addition, the compound used in the present invention may have variousisomers. For example, when a double bond is present, E form and Z formare present as geometric isomers. Moreover, tautomer can also bepresent. Further, when an optical isomer may be present as an isomer,each optical isomer and a mixture thereof are also encompassed in thepresent invention. When desired, these isomers may be optically resolvedor individually produced by a method known per se.

Accordingly, those of ordinary skill in the art should understand thatall of these isomers and mixtures thereof are encompassed in the presentinvention. The compound of the present invention is preferably isolatedand purified from various isomers, by-products, metabolites andprodrugs, and preferably has a purity of not less than 90%, morepreferably not less than 95%.

One example of the production method of the present invention isexplained in the following. However, the present invention is notlimited thereto.

Even in the absence of description in the production method, those ofordinary skill in the art will understand that an efficient productioncan be performed by employing, where necessary, introduction of aprotecting group into a functional group, removal of the protectinggroup during workup, conversion to a desired functional group at anystage and the like.

The workup after reaction in each step can be applied by a typicalmethod, wherein isolation and purification is performed by selecting orcombining conventional methods as necessary, such as crystallization,recrystallization, distillation, partition, silica gel chromatography,preparative HPLC and the like.

In the following production method and the present invention, “roomtemperature” means generally 15° C.-30° C., unless particularlydescribed.

Unless otherwise specified, the amount of the solvent to be used in thefollowing production method and the present invention is an amount thatcan be stirred in the reaction system.

The production method of compound (10) or a salt thereof, which is ananti-HIV agent (compound), from compound (1) or a salt thereof, is shownin the following scheme. Specifically, a method using compound (1-A),which is compound (1) wherein R is a methoxy group is shown as scheme 1below, and a method using compound (1-B), which is compound (1) whereinR is a fluorine atom is shown as scheme 2 below.

In the above-mentioned scheme, R¹ is a C₁-C₄ alkyl group, R² is ahydroxyl-protecting group, X¹ is a halogen atom, X² is a halogen atom,and M is a metal atom (e.g., sodium atom, potassium atom, etc.)

The compounds represented by the formulas (1), (2), (3), (4), (5) and(6) are, when R in each formula is a methoxy group, compounds (1-A),(2-A), (3-A), (4-A), (5-A) and (6-A), respectively, and when R is afluorine atom, compounds (1-B), (2-B), (3-B), (4-B), (5-B) and (6-B),respectively.

Step 1

Compound (2) or a salt thereof can be produced by reacting compound (1)or a salt thereof with a halogenating agent in a solvent.

Compound (1) and a salt thereof may be commercially available products,or can be synthesized separately according to a known technique.

Examples of the halogenating agent include brominating agents such asbromine, N-bromosuccinimide and the like, and iodinating agents such asiodine, N-iodosuccinimide and the like. A brominating agent ispreferable and bromine is more preferable.

The amount of the halogenating agent to be used is generally 1.0 to 2.0mol, preferably 1.0 to 1.2 mol, per 1 mol of compound (1).

In addition, a sulfite (e.g., sodium sulfite etc.) may be added aftercompletion of the reaction, for the purpose of treating the freehalogen.

The amount of the sulfite to be used is generally 0 to 1.1 mol,preferably 0 to 0.3 mol, per 1 mol of compound (1).

Examples of the solvent include halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike; acidic solvents such as trifluoromethanesulfonic acid, sulfuricacid, acetic acid and the like or a mixed solvent thereof and the like.An acidic solvent is preferable and acetic acid is particularlypreferable.

The reaction temperature is, when R is a methoxy group (that is, whencompound (2-A) or a salt thereof is produced from compound (1-A) or asalt thereof), generally 0° C. to 50° C., preferably 15° C. to 30° C.,and when R is a fluorine atom (that is, when compound (2-B) or a saltthereof is produced from compound (1-B) or a salt thereof), generally 0°C. to 100° C., preferably 0° C. to 70° C.

The reaction time is generally 1 hr to 48 hr, preferably 1 hr to 12 hr.When R is a methoxy group, more preferable reaction time is 1 hr to 3hr, and when R is a fluorine atom, more preferable reaction time is 1 hrto 9 hr.

Step 2

According to a conventional method, compound (3) can be obtained byreacting compound (2) or a salt thereof with a chlorinating agent in asolvent.

Compound (2) and a salt thereof can be obtained in the same manner as inthe above-mentioned step 1, and the compound wherein R is a methoxygroup, which is compound (2-A) and a salt thereof may be a commerciallyavailable product, or can be synthesized separately according to a knowntechnique.

Examples of the chlorinating agent include oxalyl chloride, phosphorusoxychloride, thionyl chloride and the like, with preference given tothionyl chloride. When oxalyl chloride or thionyl chloride is used as achlorinating agent, a catalyst (e.g., N,N-dimethylformamide etc.) may beadded.

The amount of the chlorinating agent to be used is generally 1.0 to 1.5mol, preferably 1.0 to 1.2 mol, per 1 mol of compound (2).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile and the like or a mixed solventthereof and the like. A hydrocarbon solvent is preferable and toluene ismore preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 60°C. to 80° C., more preferably 70° C. to 80° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 10 hr,more preferably 1 hr to 5 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 3

Compound (4) or a salt thereof, which is a β-ketoester, can be produced,in a solvent, in the presence of a base and a chelator, by reacting amalonic acid monoester represented by the formula (3-1) or a saltthereof (hereinafter sometimes to be abbreviated as compound (3-1)) withcompound (3), and treating the resulting compound with an acid.

Compound (3) can be obtained in the same manner as in theabove-mentioned step 2. The compound wherein R is a methoxy group, whichis compound (3-A) may be a commercially available product, or can besynthesized separately according to a known technique.

In compound (3-1), a sodium atom or a potassium atom is preferable as ametal atom for M, more preferably a potassium atom.

Compound (3-1) may be a commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably potassium ethyl malonate.

The amount of compound (3-1) to be used is generally 1 to 10 mol,preferably 1.0 to 2.0 mol, per 1 mol of compound (3).

Examples of the base include organic bases such as triethylamine,N-methylmorpholine and the like, with preference given to triethylamine.

The amount of the base to be used is generally 1 to 10 mol, preferably2.0 to 3.0 mol, per 1 mol of compound (3).

Examples of the chelator include a divalent magnesium compound (e.g.,magnesium chloride) and the like, with preference given to magnesiumchloride.

The amount of the chelator to be used is generally 1 to 10 mol,preferably 2.0 to 3.0 mol, per 1 mol of compound (3).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile and the like or a mixed solventthereof and the like. When R is a methoxy group, a preferable solvent isan ether solvent, an ester solvent or a mixed solvent thereof, morepreferably tetrahydrofuran, ethyl acetate, or a mixed solvent thereof.When R is a fluorine atom, a preferable solvent is an ether solvent, ahydrocarbon solvent or a mixed solvent thereof, more preferablytetrahydrofuran, toluene or a mixed solvent thereof.

The reaction temperature is generally 0° C. to 100° C. When R is amethoxy group, a preferable reaction temperature is 60° C. to 80° C.,more preferably 70° C. to 80° C. When R is a fluorine atom, a preferablereaction temperature is 50° C. to 80° C., more preferably 60° C. to 80°C.

The reaction time is generally 1 hr to 24 hr, preferably 2 hr to 10 hr,more preferably 2 hr to 5 hr.

Examples of the acid include acetic acid, hydrochloric acid, sulfuricacid and the like, with preference given to hydrochloric acid.

The amount of the acid to be used is not particularly limited.

The reaction temperature after the addition of the acid is generally 0°C. to 100° C., preferably 0° C. to 50° C., more preferably 15° C. to 30°C. The reaction time is generally 0.5 hr to 10 hr, preferably 0.5 hr to5 hr, more preferably 0.5 hr to 2 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 4

Compound (5) can be obtained by reacting compound (4) or a salt thereofwith a compound represented by the formula (4-1) (hereinafter sometimesto be abbreviated as compound (4-1)): N,N-dimethylformamide dimethylacetal in a solvent.

Compound (4) and a salt thereof can be obtained in the same manner as inthe above-mentioned Step 3.

Compound (4-1) may be a commercially available product, or can besynthesized separately according to a known technique.

The amount of compound (4-1) to be used is generally 1 to 10 mol,preferably 1.0 to 2 mol, particularly preferably 1.0 to 1.5 mol, per 1mol of compound (4).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile and the like or a mixed solventthereof and the like, with preference given to toluene.

The reaction temperature is generally 20° C. to 110° C. When R is amethoxy group, a preferable reaction temperature is 70° C. to 110° C.,more preferably 90° C. to 100° C. When R is a fluorine atom, apreferable reaction temperature is 50° C. to 100° C., more preferably70° C. to 90° C.

When R is a methoxy group, the reaction time is generally 1 hr to 48 hr,preferably 10 hr to 24 hr, more preferably 15 hr to 24 hr. When R is afluorine atom, the reaction time is generally 1 hr to 24 hr, preferably1 hr to 8 hr, more preferably 1 hr to 4 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 5-1

Compound (6) can be obtained by reacting compound (5) with a compoundrepresented by the formula (5-1) (hereinafter sometimes to beabbreviated as compound (5-1)):L-valinol((S)-2-amino-3-methylbutan-1-ol) in a solvent.

Compound (5-1) may be a commercially available product, or can besynthesized separately according to a known technique. The opticalpurity of compound (5-1) is not less than 95% ee, preferably not lessthan 97% ee, more preferably not less than 99% ee.

The amount of compound (5-1) to be used is generally 1 to 10 mol,preferably 1 to 2 mol, particularly preferably 1.1 to 1.3 mol, per 1 molof compound (5).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; alcoholsolvents such as methanol, ethanol, n-propanol, isopropanol and thelike; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike or a mixed solvent thereof and the like, with preference given totoluene.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., more preferably 0° C. to 30° C.

The reaction time is generally 0.5 hr to 24 hr, preferably 0.5 hr to 12hr, more preferably 0.5 hr to 3 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 5-2

When R is a methoxy group (that is, when compound (5) is compound(5-A)), compound (7-1) can be directly obtained by reacting compound(5-A) with a compound which is compound (5-1) wherein the hydroxyl groupis protected by the above-mentioned “hydroxyl-protecting group” in asolvent.

Compound (5-1) protected by the hydroxyl-protecting group can besynthesized separately according to a known technique. Examples of thecompound (5-1) protected by the “hydroxyl-protecting group” include(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine,(S)-2-methyl-1-(trimethylsilanyloxymethyl)propylamine,(S)-2-methyl-1-(tetrahydropyran-2-yloxymethyl)propylamine, methyl2-amino-3-methylbutylcarbonate and ethyl 2-amino-3-methylbutylcarbonate.It is preferably(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine,(S)-2-methyl-1-(tetrahydropyran-2-yloxymethyl)propylamine or methyl2-amino-3-methylbutylcarbonate, particularly preferably(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine.

The optical purity of compound (5-1) protected by thehydroxyl-protecting group is not less than 95% ee, preferably not lessthan 97% ee, more preferably not less than 99% ee.

The amount of compound (5-1) protected by the hydroxyl-protecting groupto be used is generally 1 to 10 mol, preferably 1 to 2 mol, particularlypreferably 1.1 to 1.3 mol, per 1 mol of compound (5-A).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; alcoholsolvents such as methanol, ethanol, n-propanol, isopropanol and thelike; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike or a mixed solvent thereof and the like, with preference given totoluene.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., more preferably 0° C. to 30° C.

The reaction time is generally 0.5 hr to 24 hr, preferably 0.5 hr to 12hr, more preferably 0.5 hr to 3 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 6

In step 6, compound (7-1) is produced by introducing a protecting groupinto a hydroxyl group of compound (6) wherein R is a methoxy group(i.e., compound (6-A)). Compound (7-1) can be obtained by introducing aprotecting group into the hydroxyl group of compound (6-A) in a solventaccording to a conventional method.

For example, when the hydroxyl-protecting group is atert-butyldimethylsilyl group, compound (7-1) can be obtained by addinga base and tert-butyldimethylsilyl chloride to compound (6-A) in asolvent.

The amount of the tert-butyldimethylsilyl chloride to be used isgenerally 1 to 10 mol, preferably 1 to 2 mol, particularly preferably 1to 1.3 mol, per 1 mol of compound (6-A).

Examples of the base include triethylamine, diisopropylethylamine,pyridine, imidazole and the like. It is preferably imidazole.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 2 mol, particularly preferably 1 to 1.3 mol, per 1 mol of compound(6-A).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile, water and the like or a mixedsolvent thereof and the like. An ether solvent, a hydrocarbon solvent, amixed solvent thereof or the like is preferable and tetrahydrofuran,toluene, a mixed solvent thereof or the like is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 15°C. to 70° C., more preferably 40° C. to 50° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 10 hr,more preferably 1 hr to 5 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 7

Compound (8) can be obtained by subjecting compound (7-1) to acyclization reaction in a solvent. A base and an additive can be addedto the reaction system.

Examples of the base include sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodiumhydride, potassium hydride, 1,8-diazabicyclo[5.4.0]-7-undecene and thelike, with preference given to potassium carbonate.

The amount of the base to be used is generally 0.5 to 10 mol, preferably0.5 to 2 mol, particularly preferably 0.5 to 1 mol, per 1 mol ofcompound (7-1).

Examples of the additive include quaternary ammonium salts such astetra-n-butylammonium bromide and the like, quaternary phosphonium saltssuch as tetra-n-butylphosphonium bromide and the like, crown ethers suchas 18-crown-6 and the like, and the like. A quaternary ammonium salt, aquaternary phosphonium salt or crown ether is preferable andtetra-n-butylphosphonium bromide is more preferable.

The amount of the additive to be used is generally 0.05 to 10 mol,preferably 0.05 to 2 mol, particularly preferably 0.05 to 1.0 mol, per 1mol of compound (7-1).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; alcoholsolvents such as methanol, ethanol, n-propanol, isopropanol and thelike; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile, water andthe like or a mixed solvent thereof and the like, with preference givento toluene.

The reaction temperature is generally 20° C. to 140° C., preferably 90°C. to 120° C., more preferably 100° C. to 110° C.

The reaction time is generally 1 hr to 24 hr, preferably 4 hr to 20 hr,more preferably 8 hr to 16 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 6′

In step 6′, compound (7-2) is produced by subjecting compound (6)wherein R is a fluorine atom (i.e., compound (6-B)) to a cyclizationreaction. A base may be added to the reaction system.

Examples of the base include sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodiumhydride, potassium hydride, 1,8-diazabicyclo[5.4.0]-7-undecene and thelike, with preference given to potassium carbonate.

The amount of the base to be used is generally 0.5 to 10 mol, preferably0.5 to 2 mol, particularly preferably 0.5 to 1 mol, per 1 mol ofcompound (6-B).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; alcoholsolvents such as methanol, ethanol, n-propanol, isopropanol and thelike; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile, water andthe like or a mixed solvent thereof and the like, with preference givento N,N-dimethylformamide (DMF).

The reaction temperature is generally 20° C. to 100° C., preferably 30°C. to 80° C., more preferably 30° C. to 60° C.

The reaction time is generally 1 hr to 24 hr, preferably 4 hr to 16 hr,more preferably 4 hr to 12 hr.

The obtained compound (7-2) can be purified by recrystallization.Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ketone solvents such as acetone, methylethylketone,methylisobutylketone and the like; ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, anisole and thelike; alcohol solvents such as methanol, ethanol, n-propanol,isopropanol and the like; polar solvents such as N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile,water and the like or a mixed solvent thereof and the like, withpreference given to a mixed solvent of ethanol and water, toluene, or amixed solvent of toluene and heptane.

Step 7′

Compound (8) can be obtained by introducing a protecting group into thehydroxyl group of compound (7-2) in a solvent according to aconventional method.

For example, when the hydroxyl-protecting group is atert-butyldimethylsilyl group, compound (8) can be obtained by adding abase and tert-butyldimethylsilyl chloride to compound (7-2) in asolvent.

The amount of tert-butyldimethylsilyl chloride to be used is generally 1to 10 mol, preferably 1 to 2 mol, particularly preferably 1 to 1.3 mol,per 1 mol of compound (7-2).

Examples of the base include triethylamine, diisopropylethylamine,pyridine, imidazole and the like, with preference given to imidazole.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 2 mol, particularly preferably 1 to 1.3 mol, per 1 mol of compound(7-2).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile, water and the like or a mixedsolvent thereof and the like, more preferably toluene.

The reaction temperature is generally 0° C. to 100° C., preferably 15°C. to 80° C., more preferably 50° C. to 80° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 10 hr,more preferably 1 hr to 5 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

For production of compound (8), of the production methods described instep 5, a compound wherein the hydroxyl group of compound (5-1) isprotected by the above-defined “hydroxyl-protecting group” is reacted,instead of compound (5-1), in the same manner as in compound (5-B), anda compound which is the obtained compound (6-B) wherein the hydroxylgroup is protected by the above-defined “hydroxyl-protecting group” isreacted in the same manner as in step 6′.

Compound (5-1) protected by a hydroxyl-protecting group can beseparately synthesized according to a known technique. Examples ofcompound (5-1) protected by a hydroxyl-protecting group include(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine,(S)-2-methyl-1-(trimethylsilanyloxymethyl)propylamine,(S)-2-methyl-1-(tetrahydropyran-2-yloxymethyl)propylamine, methyl2-amino-3-methylbutylcarbonate and ethyl 2-amino-3-methylbutylcarbonate,preferably(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine,(S)-2-methyl-1-(tetrahydropyran-2-yloxymethyl)propylamine and methyl2-amino-3-methylbutylcarbonate, particularly preferably(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine.

The optical purity of compound (5-1) protected by a hydroxyl-protectinggroup is not less than 95% ee, preferably not less than 97ee, morepreferably not less than 99% ee.

The amount of compound (5-1) protected by a hydroxyl-protecting group tobe used, is generally 1 to 10 mol, preferably 1 to 2 mol, particularlypreferably 1.1 to 1.3 mol, per 1 mol of compound (5-B).

Step 8

Compound (9) can be obtained by reacting compound (8) with a compoundrepresented by the formula (8-1) (hereinafter to be sometimesabbreviated as compound (8-1)) in a solvent in the presence of acatalyst and in the presence of a ligand as necessary.

Compound (8-1) can be separately synthesized according to ReferenceExamples 1 and 2 or a known technique.

Specifically, compound (8-1) represented by the formula (8-1) can beobtained by reacting, in advance, the metal atom with a halide and analkylsilyl compound in a solvent, and reacting the reaction mixture witha solution of substituted benzyl halide.

Examples of the substituted benzyl halide include a compound having thefollowing formula:

wherein X¹ is a halogen atom (e.g., fluorine atom, chlorine atom,bromine atom and iodine atom).

The substituted benzyl halide may be a commercially available product,or can be separately synthesized according to a known technique. It ispreferably 3-chloro-2-fluorobenzyl chloride or 3-chloro-2-fluorobenzylbromide.

Examples of the metal atom include a zinc atom and the like, preferablymetal zinc.

The metal atom is generally 1 to 5 mol, preferably 1 to 1.5 mol, per 1mol of the substituted benzyl halide.

Examples of the halide include 1,2-dibromoethane and the like,preferably 1,2-dibromoethane.

The amount of the halide to be used is 0.01 to 0.1 mol, preferably 0.01to 0.02 mol, per 1 mol of the substituted benzyl halide.

Examples of the alkylsilyl compound include trimethylsilyl chloride andthe like, preferably trimethylsilyl chloride.

The amount of the alkylsilyl compound to be used is 0.01 to 0.1 mol,preferably 0.01 to 0.05 mol, per 1 mol of the substituted benzyl halide.

Examples of the solvent include ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like;hydrocarbon solvents such as toluene, hexane, etc. and the like.Preferable solvent is an ether solvent, particularly preferably THF.

The reaction temperature is generally 0° C. to 100° C., particularlypreferably 20° C. to 65° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 12 hr,particularly preferably 3 hr to 8 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Preferable examples of compound (8-1) include3-chloro-2-fluorobenzylzinc bromide, 3-chloro-2-fluorobenzylzincchloride and a tetrahydrofuran solution thereof.

The amount of compound (8-1) to be used is generally 1 to 5 mol,preferably 1 to 2 mol, per 1 mol of compound (8).

Examples of the catalyst include palladium catalysts such asbis(dibenzylideneacetone)palladium,tris(dibenzylideneacetone)dipalladium,dichlorobis(triphenylphosphine)palladium,dichlorobis(benzonitrile)palladium, dichloroethylenediaminepalladium,palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium(II)dichloride, palladium-carbon and thelike, nickel catalyst and the like. Of these,tris(dibenzylideneacetone)dipalladium is preferable.

Examples of the ligand include triphenylphosphine,tri(2-tolyl)phosphine, tri(2-furyl)phosphine and the like, preferablytriphenylphosphine.

The amount of each of the ligand and the catalyst to be used isgenerally 0.01 to 0.1 mol, preferably 0.02 to 0.07 mol, particularlypreferably 0.02 to 0.06 mol, per 1 mol of compound (8).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogen solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike or a mixed solvent thereof and the like, preferably ether solvent,polar solvent or a mixed solvent thereof, more preferably,tetrahydrofuran, 1-methyl-2-pyrrolidinone or a mixed solvent thereof.

The reaction temperature is generally 0° C. to 100° C., preferably 40°C. to 80° C., more preferably 50° C. to 70° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 10 hr,more preferably 2 hr to 6 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

When the catalyst used is to be removed, the reaction mixture ispreferably treated with a base such as ammonium chloride, sodiumhydroxide, potassium hydroxide, lithium hydroxide, diethylenetriamine,ethylenediamine and the like, particularly preferably an aqueousammonium chloride solution or aqueous ethylenediamine solution.

Step 9

Compound (10) or a salt thereof can be obtained by subjecting compound(9) to hydrolysis in a solvent under a basic condition (e.g., in thepresence of a base such as sodium hydroxide, potassium hydroxide,lithium hydroxide and the like) or under an acidic condition (e.g., inthe presence of an acid such as hydrochloric acid, sulfuric acid and thelike).

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound (9).

The amount of the acid to be used is not particularly limited.

The reaction condition is preferably a basic condition, and the reactionis more preferably carried out in the presence of sodium hydroxide,particularly preferably using an aqueous sodium hydroxide solution.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ether solvents such as1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,anisole and the like; alcohol solvents such as methanol, ethanol,n-propanol, isopropanol and the like; polar solvents such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide, acetonitrile, water and the like or a mixed solvent thereofand the like, with preference given to a mixed solvent of isopropanoland water.

The reaction temperature is generally 0° C. to 150° C., preferably 15°C. to 100° C., more preferably 65° C. to 75° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 12 hr,more preferably 1 hr to 8 hr.

For the workup, a treatment with an activated carbon or extractionoperation can be carried out for the purpose of purifying compound (10).For example, when the reaction condition is a basic condition, theactivated carbon treatment can be carried out without any limitation onthe amount of the activated carbon to be used. Moreover, whenhydrochloric acid and the like are used for an extraction operation, theamount thereof to be used is generally 1 to 10 mol, preferably 1 to 5mol, particularly preferably 1 to 2 mol, per 1 mol of compound (9).

Examples of the solvent used in the extraction operation includehydrocarbon solvents such as toluene, xylene, hexane, heptane and thelike; ester solvents such as methyl acetate, ethyl acetate, propylacetate, isopropyl acetate, butyl acetate, isobutyl acetate and thelike; halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like; ketone solvents such asacetone, methylethylketone, methylisobutylketone, methylisopropylketoneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as acetonitrile and the like or a mixed solvent thereofand the like, with preference given to toluene, heptane, methyl acetate,ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate,isobutyl acetate, acetone, methylethylketone, methylisobutylketone,methylisopropylketone and anisole. When methylisopropylketone is used toremove impurity such as1,1′-bis-((S)-1-hydroxymethyl-2-methylpropyl)-7,7′-dimethoxy-4,4′-dioxo-1,4,1′,4′-tetrahydro-[6,6′]biquinolinyl-3,3′-dicarboxylicacid,1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid and the like, the content of the aforementioned impurity and thelike can be reduced to not more than 0.2%, preferably 0.1% to 0.2%, morepreferably not more than 0.1%, relative to compound (10). Thus, heptaneand methylisopropylketone are particularly preferable.

The obtained compound (10) can be purified by recrystallization.Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ketone solvents such as acetone, methylethylketone,methylisobutylketone and the like; ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, anisole and thelike; alcohol solvents such as methanol, ethanol, n-propanol,isopropanol and the like; polar solvents such as N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile,water and the like or a mixed solvent thereof and the like, withpreference given to a mixed solvent of ethanol and water, and toluene.

EXAMPLES

A compound useful as a synthetic intermediate for an anti-HIV agenthaving an integrase inhibitory activity and a production method thereof,and a production method of an anti-HIV agent using the syntheticintermediate are specifically explained below. Those of ordinary skillin the art will understand that the present invention is not limited tothese Examples.

Reference Example 1 Synthesis of 3-chloro-2-fluorobenzylzinc bromide

Under an argon atmosphere, a zinc powder (3.18 g) was suspended intetrahydrofuran (8 ml), 1,2-dibromoethane (0.061 g, 0.32 mmol) andtrimethylsilyl chloride (0.071 g, 0.65 mmol) were successively added at60° C., and the mixture was stirred for 30 min. A solution of3-chloro-2-fluorobenzyl bromide (7.48 g, 32.5 mmol) in tetrahydrofuran(20 ml) was added dropwise at 60° C. to the solution prepared above. Themixture was further stirred for 1 hr to give a solution of3-chloro-2-fluorobenzylzinc bromide in tetrahydrofuran.

Reference Example 2 Synthesis of 3-chloro-2-fluorobenzylzinc chloride

Under an argon atmosphere, a zinc powder (1.44 g) was suspended intetrahydrofuran (3.6 ml), 1,2-dibromoethane (38 mg) and trimethylsilylchloride (43 mg) were successively added at 60° C., and the mixture wasstirred for 30 min. A solution of 3-chloro-2-fluorobenzyl chloride (3.58g) in tetrahydrofuran (9 ml) was added dropwise at 60° C. to thesolution prepared above. The mixture was further stirred under heatingfor 1 hr to give a solution of 3-chloro-2-fluorobenzylzinc chloride intetrahydrofuran.

Example 1 Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid Step 1 Synthesis of 5-bromo-2,4-dimethoxybenzoic acid

2,4-Dimethoxybenzoic acid (30.0 g) was suspended in acetic acid (180mL). A bromine (27.6 g)/acetic acid (60 mL) solution was slowly addeddropwise to the suspension and, after completion of the dropwiseaddition, the mixture was stirred at 25° C. for 2 hrs, and thetermination of the reaction was confirmed by HPLC. An aqueous solutionof sodium sulfite (2.10 g) and water (360 mL) was added dropwise to thereaction mixture. After completion of the dropwise addition, the mixturewas stirred at 25° C. for 1 hr. Precipitated crystals were collected byfiltration, washed 4 times with water (150 mL), and vacuum dried to give5-bromo-2,4-dimethoxybenzoic acid as white crystals (41.2 g, 96%).

Step 2 Synthesis of 5-bromo-2,4-dimethoxybenzoic acid chloride

Under a nitrogen atmosphere, 5-bromo-2,4-dimethoxybenzoic acid (40.0 g)was suspended in toluene solution (DMF concentration: 300 ppm, 200 mL).To the suspension was added dropwise thionyl chloride (21.9 g) at 75° C.After stirring at 75° C. for 1 hr, completion of the reaction wasconfirmed by HPLC. toluene and excess thionyl chloride were evaporatedunder reduced pressure. Toluene (100 mL) was added to the concentratedresidue, and the mixture was concentrated again under reduced pressure.THF (100 mL) was added to the obtained 5-bromo-2,4-dimethoxybenzoic acidchloride, which was directly used in the next step.

Step 3 Synthesis of ethyl3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate

Under a nitrogen atmosphere, to a suspension of anhydrous magnesiumchloride (36.5 g) and ethyl acetate (200 mL) was slowly added dropwisetetrahydrofuran (55.2 g). After completion of the dropwise addition, themixture was stirred at 75° C. for 2 hr to dissolve anhydrous magnesiumchloride. The solution was added dropwise to an ice-cold suspension ofpotassium ethylmalonate (52.1 g) and triethylamine (46.5 g) in ethylacetate (200 mL). After the dropwise addition, the suspension was warmedto 70° C. To the suspension was slowly added dropwise at 70° C. asuspension of 5-bromo-2,4-dimethoxybenzoic acid chloride obtained inStep 2 of Example 1 in tetrahydrofuran. After completion of the dropwiseaddition, the mixture was stirred at 70° C. for 0.5 hr, and thecompletion of the reaction was confirmed by HPLC. 2N Hydrochloric acid(240 mL) was added dropwise to the reaction mixture under ice-cooling,and the mixture was stirred at room temperature for 1 hr. The organiclayer was separated, and washed successively with water (200 mL), twicewith 5% sodium hydrogencarbonate (200 mL), and water (200 mL). Afterwashing, the solvent was evaporated under reduced pressure, toluene (200mL) was added to the concentrated residue, and the mixture wasconcentrated again under reduced pressure. The obtained ethyl3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate (52.8 g) as a whitesolid was directly used in the next step.

Step 4 Synthesis of ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate

Under a nitrogen atmosphere, ethyl3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate (52.8 g) obtained inStep 3 of Example 1 and N,N-dimethylformamide dimethyl acetal (44.6 g)were dissolved in toluene. The solution was stirred at 95° C. for 16 hr,and the completion of the reaction was confirmed by HPLC. The reactionmixture was cooled to room temperature to give a solution of ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate in toluene. Thereaction mixture was directly used in the next step.

Step 5 Synthesis of ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate

Under a nitrogen atmosphere, to a solution of ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate obtained inStep 4 of Example 1 in toluene was added L-valinol (20.6 g). Afterstirring at room temperature for 1 hr, the completion of the reactionwas confirmed by HPLC. 1 mol/L Hydrochloric acid (200 mL) was added tothe reaction mixture, and after stirring, the toluene layer wasseparated. The toluene layer was further washed successively with 1mol/L hydrochloric acid (200 mL), water (200 mL), 5% aqueous sodiumhydrogencarbonate solution (200 mL) and water (200 mL). After washing,toluene was evaporated under reduced pressure, toluene (200 mL) wasadded to the concentrated residue, and the mixture was concentratedagain under reduced pressure. THF (200 mL) was further added to theconcentrated residue, and the mixture was concentrated again underreduced pressure. THF (160 mL) was added to the obtained concentratedresidue to give ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylateas a tetrahydrofuran solution. The solution was directly used in thenext step.

Step 6 Synthesis of ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropylamino)acrylate

To a solution of ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylateobtained in Step 5 of Example 1 in tetrahydrofuran was added imidazole(13.6 g) under a nitrogen atmosphere. To the solution was added at50-70° C. a 50% toluene solution (50.1 g) of tert-butyldimethylsilylchloride. After completion of the dropwise addition, the mixture wasstirred at 50-70° C. for 2 hr, and the completion of the reaction wasconfirmed by HPLC. The reaction mixture was cooled, and 1N-HCl (200 mL)was added. After the addition, the mixture was stirred at roomtemperature for 1 hr, and the organic layer was separated. The organiclayer was washed successively with 1N-HCl (200 mL), 5% NaHCO₃ (200 mL),water (200 mL), and 10% brine (200 mL). After washing, tetrahydrofuranwas evaporated under reduced pressure, toluene (200 mL) was added to theconcentrated residue, and the mixture was again concentrated underreduced pressure. Ethanol (200 mL) was further added to the concentratedresidue, and the mixture was concentrated again under reduced pressureto give crude ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropylamino)acrylateas a solid.

The crude product was recrystallized from a mixed solution of ethanol(180 mL) and water (360 mL) to give ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropylamino)acrylate(70.6 g, yield 83%, from 5-bromo-2,4-dimethoxybenzoic acid obtained inStep 1) as purified crystals.

Step 7 Synthesis of ethyl6-bromo-1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

Under a nitrogen atmosphere, ethyl2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropylamino)acrylate(5.0 g) was added to toluene (30 mL), and potassium carbonate (1.24 g)and tetra-n-butylphosphoniumbromide (1.52 g) were added. After stirringat 110° C. for 11 hr, the completion of the reaction was confirmed byHPLC. After cooling the reaction mixture, tetrahydrofuran (40 mL) and10% brine (40 mL) were added, and the toluene layer was separated. Thetoluene layer was washed twice with 10% brine (40 mL). After washing,toluene was evaporated under reduced pressure to give crude ethyl6-bromo-1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate.

The crude product was recrystallized from toluene (40 mL) to give ethyl6-bromo-1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(3.53 g, yield: 75%) as purified crystals.

Step 8 Synthesis of ethyl1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0)(332 mg) and triphenylphosphine (299 mg) were added to tetrahydrofuran(40 mL), and the mixture was stirred at room temperature for 1 hr. Ethyl6-bromo-1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(10.0 g) obtained in Step 7 of Example 1/1-methyl-2-pyrrolidinone (80ml) solution and a solution (26.2 g) of 29% 3-chloro-2-fluorobenzylzincbromide in tetrahydrofuran were successively added dropwise at roomtemperature. After completion of the dropwise addition, the mixture wasstirred at 65° C. for 3 hr, and the completion of the reaction wasconfirmed by HPLC. After cooling the reaction mixture, toluene (50 mL)and 12.5% aqueous ammonium chloride solution (100 mL) were added,sufficiently stirring, and the aqueous layer was discarded. The organiclayer was washed successively with 25% aqueous ammonium chloridesolution (50 ml), twice with 2% aqueous ethylenediamine solution (50mL), and with 10% aqueous sodium chloride solution (50 mL). Afterwashing, the solvent was evaporated under reduced pressure. Isopropanol(50 mL) was added to the concentrated residue to give a solution ofethyl1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylatein isopropanol. This was directly used in the next step.

Step 9 Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid

To a solution of ethyl1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylateobtained in Step 8 of Example 1 in isopropanol was added 1 mol/L aqueoussodium hydroxide solution (40 mL). After stirring at 70° C. for 5 hr,the completion of the reaction was confirmed by HPLC. After cooling toroom temperature, activated carbon (Sirasagi A, 1.0 g) was added to thereaction mixture. After stirring, the mixture was filtered throughpowder cellulose (KC FLOCK). The reaction vessel and the filter werewashed with isopropanol (10 mL)/water (10 mL) solution, and the lavagefluid was combined with the filtrate. Water (40 mL) and heptane (50 mL)were added to the obtained filtrate, and after stirring, the organiclayer was removed. The aqueous layer was washed again with heptane (50mL). The aqueous layer was ice-cooled, and methylisopropylketone (100mL) was added while adding concentrated hydrochloric acid (4.17 g)dropwise at 10° C. After the addition, the mixture was stirred at roomtemperature, and the aqueous layer was discarded. The organic layer waswashed successively with 8.5% aqueous sodium hydrogencarbonate solution(50 mL, twice), sodium chloride (2.5 g)/0.5 mol/L hydrochloric acid (50mL) solution, and 10% brine (50 mL). After washing, the solvent wasevaporated under reduced pressure, toluene (30 mL) was added to theobtained concentrated residue, and the mixture was concentrated againunder reduced pressure to give crude6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (9.46 g). The crude product was recrystallized from toluene (50 mL)to give6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid as purified white crystals (7.26 g, 85%).

The obtained purified6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (4.00 g) was recrystallized from ethanol (30 mL)/water (20 mL) togive a product of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (3.74 g, 94%).

The compound obtained in Step 9 of Example 1 was identified as compound(10).

TABLE 1 Structural formula ¹H-NMR MS (ESI) M+

  (10) (DMSO-d₆, 400 MHz) δ (ppm): 0.73 (d, 3H, J = 6.7 Hz), 1.16 (d,3H, J = 6.7 Hz), 2.30-2.55 (m, 1H), 3.75- 3.85 (m, 1H), 4.00-4.10 (m,1H), 4.04 (s, 3H), 4.12 (s, 2H), 4.80-4.95 (m, 1H), 5.15-5.25 (m, 1H),7.10-7.20 (m, 1H), 7.20-7.25 (m, 1H), 7.40-7.55 (m, 2H), 8.10 (s, 1H),8.94 (s, 1H), 15.5 (s, 1H). 448

The property data of the title compound in each step is as follows.

TABLE 2 Structural formula ¹H-NMR MS (ESI) M+

  (Step 1) (DMSO-d₆, 300 MHz) δ (ppm): 3.88 (s, 3H), 3.95 (s, 3H), 6.78(s, 1H), 7.86 (s, 1H), 12.47 (s, 1H). 261

  (Step 3) (DMSO-d₆, 300 MHz) δ (ppm): 1.18 (t, 3H, J = 7.3 Hz), 3.85(s, 2H), 3.87 (s, 3H), 3.96 (s, 3H), 4.12 (q, 2H, J = 7.3 Hz), 6.84 (s,1H), 7.88 (s, 1H). 331

  (Step 5) (DMSO-d₆, 300 MHz) δ (ppm): 0.82-1.00 (m, 9H), 1.85- 1.97 (m,1H), 3.20-3.42 (m, 1H), 3.47- 3.65 (m, 2H), 3.85 (s, 3H), 3.90-3.99 (m,1H), 3.89 (s, 3H), 4.95-5.00 (m, 1H), 6.70 (s, 1H), 7.27 (s, 1H), 7.98(d, 1H, J = 13.9 Hz), 10.67-10.75 (m, 1H).

  (Step 6) (DMSO-d₆, 400 MHz) δ (ppm): 0.01-0.03 (m, 6H), 0.92- 1.00 (m,10H), 0.93 (s, 9H), 1.82-1.99 (m, 1H), 3.25- 3.40 (m, 1H), 3.65-3.80 (m,1H), 3.72 (s, 3H), 3.80- 3.91(m, 2H), 3.91 (s, 3H), 6.68 (s, 1H), 7.24(s, 1H), 7.97 (d, 1H, J = 13.6 Hz), 10.60-10.73 (m, 1H). 558

  (Step 7) (DMSO-d₆, 400 MHz) δ (ppm): 0.00 ( d, 6H, J = 4.8 Hz), 0.82(s, 9H), 0.85 (d, 3H, J = 6.6 Hz), 1.24 (d, 3H, J = 6.2 Hz), 1.34 (t,3H, J = 7.3 Hz), 2.40-2.48 (m, 1H), 3.90-3.98 (m, 1H), 4.12 (s, 3H),4.12-4.17 (m, 1H), 4.23-4.34 (m, 2H), 4.80-4.87 (m, 1H), 7.47 (s, 1H),8.43 (s, 1H), 8.70 (s, 1H). 526

The analysis conditions of HPLC used in the above-mentioned Example 1are described in the following.

HPLC Analysis Conditions Analysis Method 1 (Example 1, Step 1, Step 2and Step 6) Analysis Conditions

column: AM-302 5 μm (150 mm×4.6 mm i.d.) (YMC)

column temperature: 40° C.

mobile phase:

-   -   mobile phase A: 0.01% aqueous TFA (trifluoroacetic acid)        solution    -   mobile phase B: 0.01% TFA acetonitrile solution gradient program

TABLE 3 time (min) 0 5 15 20 35 45 55 56 65 mobile 70 70 50 50 30 20 2070 stopped phase A mobile 30 30 50 50 70 80 80 30 phase B

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 55 min

Analysis Method 2 (Example 1, Step 3, Step 4 and Step 5) AnalysisConditions

column: AM-302 5 μm (150 mm×4.6 mm i.d., YMC)

column temperature: 40° C.

mobile phase:

-   -   mobile phase A: 0.01% TFA aqueous solution    -   mobile phase B: 0.01% TFA acetonitrile solution gradient program

TABLE 4 time (min) 0 15 20 35 45 46 55 mobile 55 55 50 30 30 55 stoppedphase A mobile 45 45 50 70 70 45 phase B

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 55 min

Analysis Method 3 (Example 1, Step 7) Analysis Conditions

column: Inertsil ODS-80A 5 μm (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase:

-   -   mobile phase A: 0.01% aqueous TFA solution    -   mobile phase B: 0.01% TFA acetonitrile solution gradient program

TABLE 5 time (min) 0 5 15 20 35 45 55 56 65 mobile 70 70 50 50 30 20 2070 stopped phase A mobile 30 30 50 50 70 80 80 30 phase B

flow rate: 1.0 ml/min

detection: UV 220 nm

analysis time: 55 min

Analysis Method 4 (Example 1, Step 9) Analysis Conditions

column: Inertsil ODS-80A 5 μm (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase:

-   -   mobile phase A: 10 mM phosphate buffer (pH 6.9)    -   mobile phase B: acetonitrile (HPLC grade) gradient program

TABLE 6 time (min) 0 8 25 50 51 60 mobile 55 55 20 20 55 stopped phase Amobile 45 45 80 80 45 phase B

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 55 min

Analysis Method 5 (Example 1, Step 8) Analysis Conditions

column: Inertsil ODS-80A 5 μm (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase:

-   -   mobile phase A: 10 mM phosphate buffer (pH 6.9)    -   mobile phase B: acetonitrile (HPLC grade) gradient program

TABLE 7 time (min) 0 6 8 28 35 55 56 60 mobile 50 50 40 40 20 20 50stopped phase A mobile 50 50 60 60 80 80 50 phase B

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 65 min

Example 2 Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid Step 1 Synthesis of 5-bromo-2-fluoro-4-methoxybenzoic acid

2-Fluoro-4-methoxybenzoic acid (10.0 g) was suspended in acetic acid (80mL). To the suspension was slowly added dropwise bromine (20.7 g)/aceticacid (20 mL) solution. After completion of the dropwise addition, themixture was stirred at 25° C. for 3 hr and further at 60° C. for 4 hr,the completion of the reaction was confirmed by HPLC. After cooling toroom temperature, to the suspension was added dropwise an aqueoussolution of sodium sulfite (9.63 g) and water (100 mL). After completionof the dropwise addition, the mixture was stirred at 25° C. for 2 hr,and then for 2 hr under ice-cooling. The precipitated crystals werecollected by filtration, washed four times with water (30 mL), andvacuum dried to give 5-bromo-2-fluoro-4-methoxybenzoic acid as whitecrystals (14.5 g, 99%).

Step 2 Synthesis of 5-bromo-2-fluoro-4-methoxybenzoic acid chloride

Under a nitrogen atmosphere, 5-bromo-2-fluoro-4-methoxybenzoic acid(10.0 g) was suspended in DMF/toluene solution (50 ml) (DMFconcentration: 300 ppm). To the suspension was added dropwise thionylchloride (5.73 g) at 70° C. After stirring at 70° C. for 2 hr, thecompletion of the reaction was confirmed by HPLC. Toluene and excessthionyl chloride were evaporated under reduced pressure. To theconcentrated residue was added toluene (30 ml), and the mixture wasconcentrated again under reduced pressure. To the obtained acid chloride(5-bromo-2-fluoro-4-methoxybenzoic acid chloride) was added toluene (30mL), and the mixture was directly used in the next step.

Step 3 Synthesis of ethyl3-(5-bromo-2-fluoro-4-methoxyphenyl)-3-oxopropionate

Under a nitrogen atmosphere, potassium ethylmalonate (13.7 g) andtriethylamine (12.2 g) were suspended in THF (100 mL). Furthermore,anhydrous magnesium chloride (9.56 g) was added by portions while payingattention to heat generation. The suspension was stirred at 60° C. for1.5 hr, and to the suspension was slowly added dropwise at 60° C. asuspension of acid chloride obtained in the above-mentioned Step 2 intoluene. After completion of the dropwise addition, the mixture wasstirred at 60° C. for 2 hr. The completion of the reaction was confirmedby HPLC, and the mixture was cooled to room temperature. Toluene (50 ml)was added to the reaction mixture, and 2N hydrochloric acid (60 mL) wasadded. After dropwise addition, the mixture was stirred at roomtemperature for 1 hr. The organic layer was separated, and washedsuccessively with water (50 mL), twice with 5% sodium hydrogencarbonate(50 mL), and water (50 mL). After washing, the solvent was evaporatedunder reduced pressure, toluene (50 mL) was added to the concentratedresidue, and the mixture was concentrated again under reduced pressure.To the concentrated residue was added toluene (50 mL), and a solution ofthe obtained ethyl 3-(5-bromo-2-fluoro-4-methoxyphenyl)-3-oxopropionatein toluene was directly used in the next step.

Step 4 Synthesis of ethyl2-(5-bromo-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylate

Under a nitrogen atmosphere, to a solution of ethyl3-(5-bromo-2-fluoro-4-methoxyphenyl)-3-oxopropionate obtained in theabove-mentioned Step 3 in toluene was added N,N-dimethylformamidedimethyl acetal (5.53 g). After stirring at 80° C. for 2 hr, thecompletion of the reaction was confirmed by HPLC. The reaction mixturewas cooled to room temperature to give a solution of ethyl2-(5-bromo-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylate intoluene. The reaction mixture was directly used in the next step.

Step 5 Synthesis of ethyl2-(5-bromo-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate

Under a nitrogen atmosphere, to the reaction mixture of theabove-mentioned Step 4 was added L-valinol (4.56 g). After stirring atroom temperature for 1 hr, the completion of the reaction was confirmedby HPLC. Water (50 mL) was added to the reaction mixture, and afterstirring, the toluene layer was separated. The toluene layer was furtherwashed successively with 1 mol/L hydrochloric acid (30 ml, twice), water(50 mL), 5% aqueous sodium hydrogencarbonate solution (50 mL) and 10%brine (50 mL). After washing, toluene was evaporated under reducedpressure, toluene (50 mL) was added to the concentrated residue, and themixture was concentrated again under reduced pressure. The obtainedethyl2-(5-bromo-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate(19.5 g) was directly used in the next step.

Step 6 (Corresponding to Scheme 2, Step 6′) Synthesis of ethyl6-bromo-7-methoxy-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate

Ethyl2-(5-Bromo-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate(19.5 g) was dissolved in DMF (50 mL), and potassium carbonate (8.32 g)was added. After stirring at 45° C. for 8 hr, the completion of thereaction was confirmed by HPLC. Toluene (100 mL) and 5% brine (100 mL)were added to the reaction mixture, and after stirring, the toluenelayer was separated. The toluene layer was washed 3 times with 10% brine(100 mL). After washing, toluene was evaporated under reduced pressure.Toluene (50 mL) was added to the concentrate residue, and the mixturewas concentrated again under reduced pressure. The obtained crude ethyl6-bromo-7-methoxy-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(17.4 g) was directly used in the next step.

Step 7 (Corresponding to Scheme 2, Step 7′) Synthesis of ethyl6-bromo-1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

Under a nitrogen atmosphere, ethyl6-bromo-7-methoxy-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylateobtained in the above-mentioned Step 6 and imidazole (3.55 g) weresuspended in THF (40 mL). A solution (13.3 g) of 50%tert-butyldimethylsilyl chloride in toluene was added dropwise at 65° C.After stirring at 65° C. for 1 hr, the completion of the reaction wasconfirmed by HPLC. After cooling, ethyl acetate (80 mL) and water (40mL) were added to the reaction mixture, and the organic layer wasseparated. The organic layer was washed with water (40 mL) and twice 10%brine (100 mL). After washing, the solvent was evaporated under reducedpressure to give crude ethyl6-bromo-1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(20.55 g). The crude product was recrystallized from toluene (100 mL) togive ethyl6-bromo-1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylateas purified white crystals (14.8 g, 70%).

Step 8 Synthesis of ethyl1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0)(332 mg) and triphenylphosphine (299 mg) were added to THF (40 mL), andthe mixture was stirred at room temperature for 1 hr. Ethyl6-bromo-1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(10.0 g) obtained in the above-mentioned Step 7/1-methyl-2-pyrrolidinone(80 mL) solution, and 29% CFZB (3-chloro-2-fluorobenzylzinc bromide)/THFsolution (26.2 g) were successively added dropwise at room temperature.After dropwise addition, the mixture was stirred at 65° C. for 3 hr, andthe completion of the reaction was confirmed by HPLC. After cooling,toluene (50 mL) and 12.5% aqueous ammonium chloride solution (100 mL)were added to the reaction mixture and, after sufficient stirring, theaqueous layer was discarded. The organic layer was washed successivelywith 25% aqueous ammonium chloride solution (50 mL), twice with 2%aqueous ethylenediamine solution (50 mL), and with 10% aqueous sodiumchloride solution (50 mL). After washing, the solvent is evaporatedunder reduced pressure. To the concentrated residue was addedisopropanol (50 mL) to give a solution of ethyl1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylatein isopropanol, which was directly used in the next step.

Step 9 Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid

To a solution of ethyl1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylatein isopropanol was added 1 mol/L aqueous sodium hydroxide solution (40mL). After stirring at 70° C. for 5 hr, the completion of the reactionwas confirmed by HPLC. After cooling the reaction mixture to roomtemperature, activated carbon (Sirasagi A, 1.0 g) was added. Afterstirring, the mixture was filtered through powder cellulose (KC FLOCK).The reaction vessel and the filter were washed with isopropanol (10mL)/water (10 mL) solution, and combined with the filtrate. To theobtained filtrate were added water (40 mL) and heptane (50 mL) and,after stirring, the organic layer was removed. The aqueous layer waswashed again with heptane (50 ml). The aqueous layer was ice-cooled, theconcentrated hydrochloric acid (4.17 g) was added dropwise at 10° C.,and methylisopropylketone (100 mL) was added. After the addition, themixture was stirred at room temperature, and the aqueous layer wasdiscarded. The organic layer was successively washed with 8.5% sodiumhydrogencarbonate (50 mL, twice), sodium chloride (2.5 g)/0.5 mol/Lhydrochloric acid (50 mL) solution, and 10% brine (50 mL). Afterwashing, the solvent was evaporated under reduced pressure. Toluene (30mL) was added to the obtained concentrated residue, and the mixture wasconcentrated again under reduced pressure to give crude6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (9.46 g). The crude product was recrystallized from toluene (50 mL)to give6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid as purified white crystals (7.26 g, 85%).

The above-mentioned6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (4.00 g) was recrystallized from ethanol (30 mL)/water (20 mL) togive a product of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (3.74 g, 94%).

The compound of Step 9 of Example 2 was identified as compound (10).

TABLE 8 Structural formula ¹H-NMR MS (ESI) M+

  (10) (DMSO-d₆, 400 MHz) δ (ppm): 0.73 (d, 3H, J = 6.7 Hz), 1.16 (d,3H, J = 6.7 Hz), 2.30-2.55 (m, 1H), 3.75- 3.85 (m, 1H), 4.00-4.10 (m,1H), 4.04 (s, 3H), 4.12 (s, 2H), 4.80-4.95 (m, 1H), 5.15-5.25 (m, 1H),7.10-7.20 (m, 1H), 7.20-7.25 (m, 1H), 7.40-7.55 (m, 2H), 8.10 (s, 1H),8.94 (s, 1H), 15.5 (s, 1H). 448

The property data of the title compound in each step is as follows.

TABLE 9 Structural formula ¹H-NMR MS (ESI) M+

  (Step 1) (DMSO-d₆, 300 MHz) δ (ppm): 3.87-3.97 (m, 3H), 7.14-7.17 (d,1H), 7.99-8.01 (d, 1H), 13.20 (s, 1H). 249

  (Step 5) (DMSO-d₆, 300 MHz) δ (ppm): 0.86-1.02 (m, 9H), 1.91-1.94 (m,1H), 3.53-3.60 (m, 2H), 3.89-3.97 (m, 5H), 4.96-5.01 (m, 1H), 6.99-7.05(m, 1H), 7.49-7.51 (d, 1H), 8.10-8.15 (d, 1H), 10.77- 10.86 (m, 1H).

  (Step 6) (DMSO-d₆, 400 MHz) δ (ppm): 0.74-0.75 (d, 3H), 1.11-1.15 (d,3H), 1.22-1.33 (m, 3H), 2.30 (m, 1H), 3.70-3.81 (m, 1H), 3.91 (m, 1H),4.10 (s, 3H), 4.20-4.26 (m, 2H), 4.67 (m, 1H), 5.14-5.15 (m, 1H), 7.38(s, 1H), 8.35 (s, 1H), 8.67 (s, 1H). 412

  (Step 7) (DMSO-d₆, 400 MHz) δ (ppm): 0.00 (d, 6H, J = 4.8 Hz), 0.82(s, 9H), 0.85 (d, 3H, J = 6.6 Hz), 1.24 (d, 3H, J = 6.2 Hz), 1.34 (t,3H, J = 7.3 Hz), 2.40-2.48 (m, 1H), 3.90-3.98 (m, 1H), 4.12 (s, 3H),4.12-4.17 (m, 1H), 4.23-4.34 (m, 2H), 4.80-4.87 (m, 1H), 7.47 (s, 1H),8.43 (s, 1H), 8.70 (s, 1H). 526

The analysis conditions of HPLC used in the above-mentioned Example 2are described in the following.

HPLC Analysis Conditions

Analysis Method 1 (Example 2, Step 1-Step 6) Analysis Conditions

column: Inertsil ODS-80A 5 μm (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase: mobile phase A:

-   -   0.01% TFA (trifluoroacetic acid) aqueous solution    -   mobile phase B: 0.01% TFA acetonitrile solution gradient program

TABLE 10 time (min) 0 10 20 30 31 40 mobile 55 55 20 20 55 stopped phaseA mobile 45 45 80 80 45 phase B

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 35 min

Analysis Method 2 (Example 2, Step 7 and Step 9) Analysis Conditions

column: Inertsil ODS-80A 5 in (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase:

-   -   mobile phase A: 10 mM phosphate buffer (pH 6.9)    -   mobile phase B: acetonitrile (HPLC grade) gradient program

TABLE 11 time (min) 0 8 25 50 51 60 mobile 55 55 20 20 55 stopped phaseA mobile 45 45 80 80 45 phase B

flow rate: 1.0 mL/min detection: UV 220 nm

analysis time: 55 min

Analysis Method 3 (Example 2, Step 8) Analysis Conditions

column: Inertsil ODS-80A 5 μm (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase:

-   -   mobile phase A: 10 mM phosphate buffer (pH 6.9)    -   mobile phase B: acetonitrile (HPLC grade) gradient program

TABLE 12 time (min) 0 6 8 28 35 55 56 60 mobile 50 50 40 40 20 20 50stopped phase A mobile 50 50 60 60 80 80 50 phase B

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 65 time

This application is based on a patent application Nos. 2006-60274 and2006-60297 filed in Japan, the contents of which are incorporated infull herein by this reference.

INDUSTRIAL APPLICABILITY

Compounds (6), (7-1), (7-2) and (8) of the present invention areparticularly useful as synthetic intermediates for compounds having anextremely high HIV integrase inhibitory activity (see, for example,WO2004/046115).

In addition, the present invention can provide a method of producing acompound having an HIV integrase inhibitory activity in a good yield.

Moreover, the production method of the present invention is useful as amethod for industrial mass synthesis because the method does not use ahighly dangerous and highly toxic reagent requiring careful handling andcan be performed under mild conditions.

1-71. (canceled)
 72. A compound of the following formula (7-1):

wherein R¹ is a C₁-C₄ alkyl group, R² is a hydroxyl-protecting group,and X² is a halogen atom.
 73. A compound of the following formula (6):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup, and X² is a halogen atom.
 74. A compound of the following formula(5):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup, and X² is a halogen atom.
 75. A compound of the following formula(4):

wherein R is a fluorine atom or a methoxy group, R¹ is a C₁-C₄ alkylgroup, and X² is a halogen atom, or a salt thereof.
 76. A compound ofthe following formula: